Roux-en-Y gastric bypass (RYGB) is considered by many to be the most effective treatment available for weight loss maintenance. Patients lose, on average, 25% of their body weight postoperatively for the long term, and this is accompanied by an attenuation of appetite leading to decreased caloric intake. Importantly alterations in food selection have been reported. Indeed, there is some evidence that patients decrease their preference for and intake of high sweet and high fat foods and possibly increase their preference for fruits and vegetables. Moreover, there are many anecdotal reports from patients that they experience changes in taste sensibility. Taste indisputedlty guides food choices and the effect of RYGB on gustatory processes may promote a shift to a lower glycemic index diet and potentially contribute to the weight loss and health gain. However, the literature, which is dominated by measures of verbal report such as dietary recall, is mixed, with some studies finding changes and others not. Our strategy to studying RYGB-induced taste and motivational changes has been to take a coordinated approach to the problem by conducting parallel experiments in both our established rat model and our human bariatric clinical research program at Imperial College London. Our view is that disparities in the literature could be more effectivel resolved by complementing the collection of existing findings with more direct measures of target behaviors in humans that can also be applied to our animal model. Accordingly, our first objective is to use our animal model to follow up our promising preliminary findings suggesting that RYGB in humans decreases the motivation to work for food reward as demonstrated by a decrease in breakpoint (the point at which animals cease working for reward) in a progressive ratio task (in which each subsequent reward delivery requires a progressively greater number of responses). We wish to establish whether rats will display similar modulation of breakpoint after RYGB and, importantly, whether this effect depends on the orosensory characteristics of the reward. The progressive ratio task is a pure measure of appetitive behavior and is designed for applications in which the reinforcer delivery needs to be limited to obviate satiation. As such, itis well suited for assessing changes in the reward value of simple and complex taste stimuli after RYGB, while rendering the potential effects of the postingestive load negligible. Our second objective is to begin to study potential underlying physiological mechanisms. After RYGB, circulating levels of key anorexogenic gastrointestinal hormones such as peptide YY and glucagon-like peptide-1 increase. Systemic administration of the somatostatin analog, octreotide, which blocks the release of these and other gut hormones, doubles short-term chow intake in rats after RYGB, but has no effects in SHAM-operated controls. Thus, we will test whether changes in the reward value of specific nutritionally relevant stimuli might be reversed by octreotide, paving the way for more selective mechanistic manipulations in future work. PUBLIC HEALTH RELEVANCE: Close to 100,000 gastric bypass operations are performed in the US every year, and it is considered by many to be one of the most effective treatments available for long-term body weight loss. The mechanisms promoting and maintaining the weight loss are not well understood. The proposed research will objectively examine whether gastric bypass changes the taste palatability of specific types of foods helping to promote a more healthy diet and begin to test the role of gut hormones in these anticipated effects. Ultimately, our long-range goal is to contribute to the development of less invasive interventions to treat and prevent obesity and its associated disorders.